Natural and synthetic alkaloids of opium (i.e., opioids) are useful as analgesics for the treatment of severe pain. Opioids target three types of endogenous opioid receptors: μ-, δ-, and κ-receptors. Many opioids, such as morphine, are μ-receptor agonists that are highly efficacious analgesic compounds due to their activation of opioid receptors in the brain and central nervous system (CNS). Opioid receptors are, however, not only limited to the CNS, but may be found in other tissues throughout the body. These receptors located outside the CNS are referred to as peripheral receptors. A number of side effects associated with opioid use are caused by activation of these peripheral receptors. For example, administration of opioid agonists often results in intestinal dysfunction due to action of the opioid agonist upon the large number of receptors in the intestinal wall. Specifically, opioids are generally known to cause nausea and vomiting as well as inhibition of normal propulsive gastrointestinal function in animals, resulting in side effects such as constipation.
Opioid-induced side effects are a serious problem for patients being administered opioid analgesics for both short term and long term pain management. For instance, more than 250,000 terminal cancer patients each year take opioids, such as morphine, for pain relief, and about half of those patients experience severe constipation. In many situations the discomfort can be so great that the patients choose to forego the pain relief in order to avoid the constipation. In an effort to address this problem, certain opioid antagonist compounds that do not readily cross the blood-brain barrier have been tested for use in curbing opioid-induced side effects. For instance, the peripheral μ-opioid antagonist compound, methylnaltrexone, and related compounds have been suggested for use in assuaging opioid-induced side effects. See for example, U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215, which describe the use of methylnaltrexone and related compounds in controlling opioid-induced pruritus, nausea, and/or vomiting. Methylnaltrexone, however, is an experimental drug and is not commercially available. Unfortunately, most of the currently available opioid antagonists, such as the tertiary opioid antagonist, naloxone, are small molecules that not only possess antagonist activity at peripheral receptors associated with the intestine, but also possess antagonist activity at CNS receptors since they cross the blood-brain barrier. Consequently, many opioid antagonists interfere with the pain relief brought about by administration of opioid-based analgesics. Thus, at present, patients receiving opioid pain medications face the difficult choice of suffering burdensome adverse effects such as constipation or ineffective analgesia.
Thus, there is a need in the art for alternative compounds, or for approaches for modifying or improving upon existing compounds, that can reduce or eliminate opioid-induced side effects such as constipation, even when administered in high doses, without interfering with the pain-suppressing effects of the opioid.